ATL is caused by the HTLV-1 retrovirus but it is unknown how this virus leads to cellular transformation. The only HTLV-1 gene product that is expressed in all ATL cells is HBZ but exactly how HBZ transforms T lymphocytes is unclear. Using genomic scale RNA interference, we identified a regulatory network involving the transcription factors BATF3 and IRF4 that is essential for ATL proliferation and survival. Through the use of available gene expression profiling data, we showed that BATF3/IRF4 downstream targets area a hallmark of ATL that distinguishes it from other T-cell lymphoma subsets. We showed that BATF3/IRF4 are essential for ATL proliferation on our master regulators of gene expression in ATL cell lines in patient samples. Furthermore, we showed that HBZ upregulates expression of BATF3 and its target genes by binding to an ATL specific BAFT3 super-enhancer. BET protein inhibitors collapse the transcriptional network directed by HBZ and BATF3/IRF4. BET protein inhibitors are toxic for ATL cell line in patient samples ex vivo and block ATL xenograft growth. Our preclinical studies provide a solid rationale for the initiation of clinical trials of BET inhibitors in ATL. In additional studies, we demonstrated that disorders of common gamma cytokine receptor JAK/STAT pathway are pervasive in T-cell malignancy. As assessed by pSTAT3/pSTAT5 phosphorylation and nuclear translocation there is a proportion of from rare to 86% of virtually all subsets of T-cell lymphoma that manifest such activation of the pathway. In these T-cell malignancies with an activated JAK/STAT pathway activating mutations of STAT3/STAT5B, JAK1, JAK3 were frequent but not sufficient to initiate proliferation and only augmented signals from the cytokine receptor JAK/STAT pathway. pSTAT malignant T-cell lines were addicted to JAK1 and JAK3 whether or not they were mutated. Even with activating JAK mutations there was a requirement for expression of a functional cytokine receptor that played two roles, first as a scaffold for cross-activation of JAK kinases and second as a docking site for recruitment of STAT transcription factors. These studies support the development of a pure JAK1 or pure JAK3 inhibitor as an element in multidrug therapy of T-cell malignancy. A major focus of the Waldmann/Staudt Laboratory is to define molecular abnormalities of HTLV-1 associated ATL. Previously we demonstrated that HTLV-1 encoded Tax transactivates two autocrine (IL-2/IL-2R, IL-15/IL-15R alpha) and one paracrine (IL-9) pathway. To extend these observations we performed molecular interference Achilles' heel screening of ATL cell lines employing a library of retroviral vectors for inducible expression of short-hairpin RNAs (shRNAs) to identify genes essential for leukemic cell survival. Using this loss-of-function screen, 6 of 7 distinct cytokine-dependent ATL cell lines were shown to be critically dependent on JAK1 and JAK3 for proliferation and survival. The critical nature of the gamma cytokine, JAK1/JAK3 pathway for ATL was supported by our observation that the ex vivo 6-day culture of PBMCs from patients with smoldering and chronic ATL could be inhibited by the administration of antibodies to the IL-2 receptor, as well as by the pan-JAK inhibitor, tofacitinib and the JAK1/2 inhibitor, ruxolitinib. To translate these observations, the Waldmann, Conlon and Miljkovic Group has initiated a phase II clinical trial involving the JAK1/2 inhibitor, ruxolitinib in patients with ATL. However, ruxolitinib was not adequate in that it had a short in vivo survival. When ruxolitinib was given orally there was an inhibition of STAT phosphorylation for only 1 to 3 hours for the 12-hour period between dosings. Furthermore, there was off-target inhibition of JAK2 that would lead to thrombocytopenia if ruxolitinib were given in adequate doses. To address this issue, we have demonstrated that the JAK3 inhibitor (PF-06651600 of Pfizer) is specific for JAK3 and does not inhibit JAK2. Furthermore, it inhibits the JAK/STAT pathway as assessed by STAT phosphorylation for at least 24 hours. In yet other studies in translation of the observation that CCR4 is expressed by 95% of ATL cells we used it as the target of a collaborative clinical trial involving patients with ATL using the anti-CCR4 monoclonal antibody, mogamulizumab. Furthermore, Liyanage Perera in the Waldmann Laboratory has generated an anti-CCR4 CAR for use in clinical trials of patients with ATL to take advantage of the over 90% CCR4 expression on ATL leukemic cells. In summary, the Waldmann Laboratory has made major contributions concerning the translation of molecular insights concerning ATL into new novel therapeutic strategies for this malignancy and a greater understanding of the retroviruses' mechanisms of action. In new studies we demonstrated bifurcation of signals for NK-cell survival and proliferation by trans-endocytosed versus soluble IL-15R alpha-IL-15 complexes. We showed here that the entire membrane associated IL-15R alpha-IL-15 complex was transferred from presenting cells to NK cells through endocytosis and that this stimulated efficient phosphorylation of ribosomal protein S6 and proliferation. Conversely NK cell interaction with IL-15R alpha to IL-15 that was either surface bound or shed in soluble form resulted in preferential STAT5 phosphorylation and NK survival. These studies provided a mechanism for NK cell expansion that is not available to soluble IL-2 and has profound implication for the stimulation and use of NK cells in cancer immunotherapy.